The gonadotropin-releasing hormone (GnRH) is a hormone that is synthesized predominantly but not exclusively in mammals by nerve cells of the hypothalamus, is transported via the portal vein to the hypophysis and is released in a regulated manner to the gonadotropic cells. By interaction with its receptor that has seven transmembrane domains, GnRH stimulates the production and the release of gonadotropic hormones by means of the second messenger inositol-1,4,5-triphosphate and Ca2+ ions. The gonadotropin-luteinizing hormone (LH) that is released by GnRH and the follicle-stimulating hormone (FSH) stimulate the production of sex steroids and the gamete maturation in both sexes. In addition to GnRH (also referred to as GrRH1), there are two other forms of GnRH, namely GnRH2 and 3.
The GnRH receptor is used as a pharmacological target in a number of diseases that are dependent on a functioning sex hormone production, for example prostate cancer, premenopausal breast cancer, endometriosis and uterine fibroids. In the case of these diseases, GnRH superagonists or GnRH antagonists can be used successfully. In particular, the male birth control in combination with a substitution dose of androgens forms a possible further indication.
An advantage of GnRH antagonists in comparison to superagonists is their immediate effectiveness in the blocking of the gonadotropin secretion. Superagonists initially produce an overstimulation of the hypophysis, which results in increased gonadotropin and sex steroid releases.
This hormonal reaction is only completed after a certain delay based on the desensitization and downward-adjustment of the GnRH receptor concentrations. Therefore, GnRH superagonists, both alone and in combination with testosterone, may not be able to suppress effectively sperm production in males and thus are not suitable for male birth control. In contrast to this, peptide GNRH antagonists, especially in combination with a substitution dose of androgen, are able to bring about a significant oligozoospermia in humans.
Peptide GnRH antagonists, however, have a number of drawbacks. They have a considerably lower effectiveness as superagonists and consequently have to be administered at considerably higher dosages. Their oral bio-availability is also low, so that they have to be administered by injection. Repeated injections lead in turn to a reduction in compliance. Moreover, the synthesis of peptide GnRH antagonists in comparison to non-peptide compounds is costly and labor-intensive.
Quinoline derivatives as non-peptide GnRH antagonists are disclosed in, for example, WO97/14682. To date, however, it was not possible to market any non-peptide GnRH antagonists.
The object on which this invention is based consisted in providing new GnRH antagonists that are superior to the known peptide compounds and represent an effective alternative to known non-peptide compounds. The new GnRH antagonists are to have both high effectiveness and high oral bio-availability. In addition, they should be able to be synthesized simply and with as low costs as possible.
This object is achieved by compounds of general formula (1): 
in which
R1 (a) is an acyl group xe2x80x94COxe2x80x94R11 or CN, whereby R11 is a saturated, unsaturated, cyclic and/or (hetero)aromatic organic radical, especially a straight or branched alkyl chain with 1-10 C atoms or a phenyl, furan or thiophene group that is optionally substituted by alkyl groups or halogen atoms,
xe2x80x83(b) is a carboxylic acid ester group xe2x80x94COxe2x80x94OR12 or a carboxylic acid amide group xe2x80x94COxe2x80x94NR12R13 or a group xe2x80x94SOxxe2x80x94R12 with X=0, 1 or 2 or xe2x80x94SO2xe2x80x94NR12R13, whereby R12 is a saturated, unsaturated, cyclic and/or (hetero)aromatic organic radical, especially a straight or branched alkyl chain with 1-10 C atoms, an aralkyl group with 7-20 C atoms, whereby the aryl radical optionally can be substituted by alkyl groups or halogen atoms or is a phenyl radical that is optionally substituted by alkyl groups or halogen atoms, and R13 can be a hydrogen atom or a straight or branched alkyl chain with 1-10 C atoms, or
xe2x80x83(c) is the group xe2x80x94Axe2x80x94NR14-COxe2x80x94NR15R16, in which A is an alkylene group with 1-4 C atoms, especially with 1 C atom, that is optionally substituted by a C1-C6 alkyl group, a carbonyl group, an oxygen atom or the group xe2x80x94SOxxe2x80x94 with X=0, 1 or 2; R14 and R15, in each case independently are a hydrogen atom or a straight or branched alkyl chain with 1-10 C atoms, and R16 is a straight or branched alkyl chain with 1-10 C atoms, a cycloalkyl group with 3-10 C atoms, a cycloalkylalkyl group with 7-20 C atoms, an aralkyl group with 7-20 C atoms, whereby the aryl radical optionally can be substituted by alkyl groups or halogen atoms, a phenyl group that is optionally substituted by alkyl groups or halogen atoms or a heterocyclic ring that is optionally substituted by alkyl groups or halogen atoms,
R2 is a group xe2x80x94CH(R21)R22, whereby R21 is a hydrogen atom, a C1-C10-alkyl group or an optionally substituted phenyl ring and R22 is an optionally substituted phenyl ring or naphthyl ring, or a group xe2x80x94CH2CH(R23)R24, with R23 and R24 in the meaning of an optionally substituted phenyl ring,
R3 and R4 in each case independently are a hydrogen atom or an alkyl group with 1-10 C atoms, and R3 also can be a halogen atom,
R5 is a group that is linked via radical Z, 
xe2x80x83in which G is xe2x80x94Cxe2x95x90Cxe2x80x94, xe2x80x94Cxe2x95x90Nxe2x80x94, xe2x80x94Nxe2x95x90Cxe2x80x94, an oxygen or sulfur atom; Z is a direct bond, an oxygen atom or a sulfur atom, the group CHxe2x80x94R52 or xe2x80x94CHxe2x80x94R52-CHxe2x80x94R53-, whereby R52 and R53, independently of one another, have the meaning of a hydrogen atom or an alkyl group and n means numbers 1 and 2, a xe2x80x94Cxe2x89xa1C-triple bond or an E- or Z-configured group xe2x80x94CR52=CR53- or Cxe2x95x90CR52R53, whereby R52 and R53, independently of one another, have the meaning of a hydrogen atom or an alkyl group, L is a CH2 group or an NH group, Q is a carbonyl or xe2x80x94SOx group, with X=0, 1 or 2, and R51 is an amino group that is optionally substituted by an alkyl group or a straight or branched alkyl group that is optionally substituted by halogen atoms, hydroxyl or alkoxy groups, or a cycloalkyl group with 3-7 ring members that is optionally substituted by halogen atoms, hydroxyl or alkoxy groups,
R6 is the group CH2xe2x80x94N(R61)R62, whereby R61, in each case independently, is a hydrogen atom or an alkyl group, and R62 is an alkyl group or an optionally substituted aralkyl group or a heteroarylalkyl group with 7-20 C atoms, and can mean
xe2x80x94Wxe2x95x90Xxe2x95x90Yxe2x80x94xe2x80x94 the groups 
xe2x80x83in any orientation; also all stereoisomers of the above-mentioned structures and salts thereof with physiologically compatible acids or bases.
In the compounds of formula (1), by way of example
R1 means:
xe2x80x83A straight or branched alkyl chain: A methyl, ethyl, n-propyl, iso-propyl, n-, iso-, tert-butyl, n-pentyl, 2,2-dimethylpropyl or 3-methylbutyl group; an n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl group. The methyl or ethyl group is preferred.
xe2x80x83A phenyl group that is optionally substituted by alkyl groups or halogen atoms: A phenyl group; an o-, m-, p-methyl, ethyl, propyl, or isopropylphenyl group; a 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5-dimethyl or -diethylphenyl group; an o-, m-, p-fluoro-, chloro-, bromo- or iodophenyl group; a 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5-, difluoro-, dichloro-, dibromo- or diodophenyl group or a naphthyl group. A phenyl group is preferred.
xe2x80x83An optionally substituted furan or thiophene group: An unsubstituted 2- or 3-thienyl group; or a 2- or 3-furyl group; or a 3-methyl-, 3-ethyl-, 3-fluoro-, 3-chloro-, 3-bromo-, 3-iodo-2-furyl- or -2-thienyl group; a 4-methyl-, 4-ethyl-, 4-fluoro-, 4-chloro-, 4-bromo-, 4-iodo-2-furyl- or 2-thienyl group; a 5-methyl-, 5-ethyl-, 5-fluoro-, 5-chloro-, 5-bromo-, 5-iodo-2-furyl or -2-thienyl group; a 2-methyl-, 2-ethyl-, 2-fluoro-, 2-chloro-, 2-bromo-, 2-iodo-3-furyl or -3-thienyl group; a 4-methyl-, 4-ethyl-, 4-fluoro-, 4-chloro-, 4-bromo-, 4-iodo-3-furyl- or -3-thienyl group; a 5-methyl-, 5-ethyl-, 5-fluoro-, 5-chloro-, 5-bromo-, 5-iodo-3-furyl- or -3-thienyl group. Preferred is a 2-thienyl or 2-furyl group.
xe2x80x83An aralkyl group with 7-20 C atoms: A benzyl group; a 1-phenyl-ethyl-, -propyl-, -butyl-, -hexyl-, -2-methylethyl-, -2-ethylethyl-, -2,2-dimethylethyl group; an o-, m-, p-methyl, ethyl, propyl, isopropylbenzyl group; a 2xe2x80x2,3xe2x80x2-, 2xe2x80x2,4xe2x80x2-, 2xe2x80x2,5xe2x80x2-, 2xe2x80x2,6xe2x80x2-, 3xe2x80x2,4xe2x80x2-, 3xe2x80x2,5xe2x80x2-dimethyl- or -diethylbenzyl group; a 2xe2x80x2-, 3xe2x80x2-, 4xe2x80x2-fluoro-, chloro-, bromo-, iodobenzyl group; a 2xe2x80x2,3xe2x80x2-, 2xe2x80x2,4xe2x80x2-, 2xe2x80x2,5xe2x80x2-, 2xe2x80x2,6xe2x80x2-, 3xe2x80x2,4xe2x80x2-, 3xe2x80x2,5xe2x80x2-, difluoro, dichloro-, dibromo- or diiodobenzyl group or a 2- or 3-naphthylmethyl group; a 2-phenylethyl-, 3-phenyl-propyl-, 4-phenylbutyl-, or 5-phenylpentyl group.
xe2x80x83A C1-C6 alkyl group: A straight or branched alkyl group with 1-6 C atoms, such as a methyl, ethyl, n-propyl, iso-propyl, n-, iso-, tert-butyl, n-pentyl, 2,2-dimethylpropyl or 3-methylbutyl group.
xe2x80x83A cycloalkyl radical: A cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, or decahydronaphthalene radical.
xe2x80x83A cycloalkylalkyl radical: A cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl-methyl radical; a 1-cyclopropyl, 1-cyclobutyl, 1-cyclopentyl, 1-cyclohexyl, 1-cycloheptyl-ethyl radical; a 2-cyclopropyl, 2-cyclobutyl, 2-cyclopentyl, 2-cyclohexyl, or 2-cycloheptyl-ethyl radical.
xe2x80x83A heterocyclic ring: An unsubstituted 2- or 3-thienyl group or a 2- or 3-furyl group or a 3-methyl-, 3-ethyl-, 3-fluoro-, 3-chloro-, 3-bromo-, 3-iodo-2-furyl- or -2-thienyl group; a 4-methyl-, 4-ethyl, 4-fluoro-, 4-chloro-, 4-bromo-, 4-iodo-2-furyl or -2-thienyl group; a 5-methyl-, 5-ethyl-, 5-fluoro-, 5-chloro-, 5-bromo-, 5-iodo-2-furyl- or -2-thienyl group; a 2-methyl, 2-ethyl, 2-fluoro-, 2-chloro-, 2-bromo-, 2-iodo-3-furyl or -3-thienyl group; a 4-methyl-, 4-ethyl-, 4-fluoro-, 4-chloro-, 4-bromo-, 4-iodo-3-furyl- or -3-thienyl group; a 5-methyl-, 5-ethyl-, 5-fluoro-, 5-chloro-, 5-bromo-, 5-iodo-3-furyl- or -3-thienyl group; an unsubstituted 2-, 3- or 4-pyridyl group or a 3-methyl-, 3-ethyl-, 3-fluoro-, 3-chloro-, 3-bromo-, 3-iodo-2-pyridyl group; a 4-methyl-, 4-ethyl-, 4-fluoro-, 4-chloro-, 5-bromo-, 4-iodo-2-pyridyl group; a 5-methyl-, 5-ethyl-, 5-fluoro-, 5-chloro-, 5-bromo-, 5-iodo-2-pyridyl group; a 2-methyl-, 2-ethyl-, 2-fluoro-, 2-chloro-, 2-bromo-, 2-iodo-3-pyridyl group; a 4-methyl-, 4-ethyl-, 4-fluoro-, 4-chloro-, 4-bromo-, 4-iodo-3-pyridyl group; a 5-methyl-, 5-ethyl-, 5-fluoro-, 5-chloro-, 5-bromo-, 5-iodo-3-pyridyl group; a 2-, 4-, 5-, 6-pyrimidinyl group; a 3-, 4-, 5-, 6-pyridazinyl group or a 2- or 3-pyrazinyl group.
R2 means:
xe2x80x83An alkyl group: A straight or branched alkyl group with 1-6 C atoms, such as a methyl, ethyl, n-propyl, iso-propyl, n-, iso-, tert-butyl, n-pentyl, 2,2-dimethylpropyl or 3-methylbutyl group. A hydrogen atom is preferred.
xe2x80x83An optionally substituted phenyl ring or naphthyl ring: a phenyl group; an o-, m-, p-methyl, -ethyl, -propyl-, isopropylphenyl group; a 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5-dimethyl- or -diethylphenyl group; an o-, m-, p- fluoro-, chloro-, bromo-, or iodophenyl group; a 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5-difluoro-, dichloro-, dibromo- or diiodophenyl group; an o-, m-, p-trihalomethylphenyl group; a 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5 di-trihalogen-phenyl group; an o-, m-, p-methoxy, -ethoxy, -propoxy, -isopropoxyphenyl group or a naphthyl group. A 2,5-difluorophenyl group is preferred.
R3 and R4 mean:
xe2x80x83An alkyl group: A straight or branched alkyl group with 1-6 C atoms, such as a methyl, ethyl, n-propyl, iso-propyl, n-, iso-, tert-butyl, n-pentyl, 2,2-dimethylpropyl- or 3-methylbutyl group. A hydrogen atom is preferred.
R5 means:
xe2x80x83An alkyl group: A straight or branched alkyl group with 1-6 C atoms, such as a methyl-, ethyl-, n-propyl-, iso-propyl-, n-, iso-, tert-butyl-, n-pentyl-, 2,2-dimethylpropyl- or 3-methylbutyl group. A hydrogen atom is preferred.
R6 means:
xe2x80x83An alkyl group: A straight or branched alkyl group with 1-6 C atoms, such as a methyl-, ethyl-, n-propyl-, iso-propyl-, n-, iso-, tert-butyl-, n-pentyl-, 2,2-dimethylpropyl- or 3-methylbutyl group. A methyl group is preferred.
xe2x80x83An aralkyl group with 7-20 C atoms: A benzyl group; a 1-phenyl-ethyl-, -propyl-, -butyl-, -hexyl-, -2-methylethyl-, -2-ethylethyl-, or -2,2-dimethylethyl group; an o-, m-, p-methyl-, ethyl-, propyl-, or isopropylbenzyl group; a 2xe2x80x2,3xe2x80x2-, 2xe2x80x2,4xe2x80x2-, 2xe2x80x2,5xe2x80x2-, 2xe2x80x2,6xe2x80x2-, 3xe2x80x2,4xe2x80x2-, 3xe2x80x2,5xe2x80x2-dimethyl- or -diethylbenzyl group; a 2xe2x80x2-, 3xe2x80x2-, 4xe2x80x2-fluoro-, chloro-, bromo-, or iodobenzyl group; a 2xe2x80x2,3xe2x80x2-, 2xe2x80x2,4xe2x80x2-, 2xe2x80x2,5xe2x80x2-, 2xe2x80x2,6xe2x80x2-, 3xe2x80x2,4xe2x80x2-, 3xe2x80x2,5xe2x80x2-, difluoro-,
dichloro-, dibromo- or diiodobenzyl group or a 2- or 3-naphthylmethyl group; a 2-phenylethyl-, 3-phenylpropyl-, 4-phenylbutyl, or 5-phenylpentyl group.
xe2x80x83A heteroaralkyl group with 7-20 C atoms: A 2-, 3- or 4-pyridyl-methyl-, -ethyl- or -propyl group; a 2- or 3-furyl-methyl-, -ethyl-, or -propyl group; a 2- or 3-thienyl-methyl-, -ethyl- or -propyl group; a 2-, 3-, 4-, 5-, 6-, or 7-indolyl-methyl-, -ethyl- or -propyl group. The benzyl group is preferred.
Preferred are compounds of formula (I), in which
W31 xe2x88x92Xxe2x88x92xe2x88x92Yxe2x80x94 is the group 
If R1 is group xe2x80x94COxe2x80x94R11, then R11 has, for example, the preferred meaning of methyl, ethyl, i-propyl, phenyl, 2-thienyl and 2-furyl. If R1 has the meaning of xe2x80x94COxe2x80x94OR12, then R12 can be, for example, preferably methyl, ethyl or i-propyl.
In addition, compounds are preferred in which R2 is an aromatic group, e.g., a benzyl group, for example a 2xe2x80x2,6xe2x80x2-difluorobenzyl group, that is substituted on the aromatic ring by one or more halogen atoms, especially fluorine atoms. Also preferred are compounds in which at least one of R3 and R4, especially both, are hydrogen atoms.
A preferred meaning of Z is a direct bond or an oxygen atom, while G preferably means a xe2x80x94Cxe2x95x90C group. L is preferably an NH group, while Q preferably is a carbonyl group and R51 is a C1-C6 allyl group. Especially preferred meanings of R61 are hydrogen atoms or C1-C3 alkyl groups, especially methyl groups, and an especially preferred meaning of R62 is an aralkyl radical, e.g., a benzyl group.
The production of compounds (1) is preferably carried out
(a) By reaction of a compound of general formula (2) 
xe2x80x83whereby R7 means a leaving group, e.g., a halogen atom or an alkyl, perfluoroalkyl or arylsulfonyl group, and all other radicals have the meaning that is indicated in compound (1), with a compound of general formula (3)
R8-N(R61)R62xe2x80x83xe2x80x83(3)
xe2x80x83whereby R8 means a hydrogen atom or a metal atom, such as, e.g., a lithium, sodium, potassium, cesium, calcium or barium atom, and R61 and R62 have the meanings that are indicated in compound (1),
(b) By reaction of a compound of general formula (4) 
xe2x80x83in which R9 is the group xe2x80x94OSO2CnF2n+1, a halogen atom, especially a bromine or iodine atom, or another leaving group, and all other radicals have the meaning that is indicated in compound (1), with a compound of general formula (5) 
xe2x80x83whereby R10 is a group that contains a metal, such as a group that contains a trialkyltin group, a halomagnesium group or a group that contains a non-metal, such as boron, silicon, etc.; a dialkoxyboron group or a dihydroxyboron group; a hydroxy or mercapto group that is optionally converted into a metal salt, such as, e.g., a lithium, sodium, potassium, cesium, calcium, barium, silver or copper salt; the group xe2x80x94Cxe2x89xa1Cxe2x80x94R31 or an E- or Z-configured group xe2x80x94CR52=CR53R31 or xe2x80x94CR31=CR52R53, in which R31 is a group that contains a metal or a non-metal, such as boron, silicon, etc., such as a trialkyltin group, a halomagnesium group, a dialkoxyboron group or a dihydroxyboron group, and all other radicals have the meaning that is indicated in compound (1), with or without the involvement of a catalyst, such as, e.g., copper, nickel, palladium, platinum or organic derivatives of the above-mentioned metals;
(c) If Y is a nitrogen atom in compound (1), by reaction of a compound of general formula (6) 
xe2x80x83whereby R32 means a hydrogen atom or a metal atom, such as, e.g., a lithium, sodium, potassium, cesium, calcium, barium, silver or copper atom, and all other radicals have the meaning that is indicated in compound (1), with a compound of general formula (7)
R33-R2xe2x80x83xe2x80x83(7)
xe2x80x83whereby R33 means a leaving group, e.g., a halogen atom or an alkyl, perfluoroalkyl or arylsulfonyl group, and R2 has the meaning that is indicated in compound (1) or
(d) If W in compound (1) is a nitrogen atom, by reaction of a compound of general formula (8) 
xe2x80x83whereby R32 means a hydrogen atom or a metal atom, such as, e.g., a lithium, potassium, cesium, calcium, barium, silver or copper atom, and all other radicals have the meaning that is indicated in compound (1), with a compound of general formula (9)
R33-R1xe2x80x83xe2x80x83(9)
xe2x80x83whereby R33 means a leaving group, e.g., a halogen atom or an alkyl, perfluoroalkyl or arylsulfonyl group, and R1 has the meaning that is indicated in compound (1).
Compounds (1) according to the invention can be used as antagonists of the gonadotropin-releasing hormone, for example for male birth control, for hormone therapy, for treatment of female subfertility and infertility, for female contraception and to combat tumors.
In male birth control, the compounds according to the invention bring about a reduction in spermatogenesis. A combined administration with androgens, e.g., testosterone or testosterone derivatives, such as, for example, testosterone esters, preferably takes place. The administration of testosterone derivatives can be carried out, for example, by injection, e.g., by intramuscular depot injection.
Compounds (1), optionally in combination with other hormones, e.g., estrogens and/or progestins, can also be used in hormone therapy, for example for treating endometriosis, uterus leiomyomas and uterine fibroids. Especially preferred are combinations of the GnRH antagonists according to the invention and tissue-selective partial estrogen agonists such as Raloxifene(copyright). Moreover, compounds (1) according to the invention can be used for increasing female fertility, for example by inducing ovulation, and treating sterility.
In contrast, compounds (1) are also suitable for contraception in females. Thus, the GnRH antagonist can be administered on days 1 to 15 of the cycle together with estrogen, preferably with very low estrogen dosages. On days 16 to 21 of the intake cycle, progestagen is added to the estrogen-GnRH-antagonist combination. The GnRH antagonist can be administered continuously over the entire cycle time. In this way, a reduction in the hormone dosages and thus a reduction in the side effects of unphysiological hormone levels can be achieved. In addition, advantageous effects in women who suffer from polycystic ovarian syndrome and androgen-dependent diseases, such as acne, seborrhea and hirsutism, can be achieved. An improved cycle monitoring relative to previous administration methods can also be expected. Further indications are benign prostate hyperplasia, gonad protection in chemotherapy, controlled ovarian stimulation/artificial reproduction techniques, and infantile development disorders, e.g., Pubertas praecox and polycystic ovaries.
Finally, the GnRH agonists according to the invention can also be used for the treatment of hormone-dependent tumor diseases, such as premenopausal breast cancer, prostate cancer, ovarian cancer and endometrial cancer, by the endogenous sex steroid hormones being suppressed.
Compounds (1) according to the invention are suitable as GnRH antagonists for administration to humans, but also for the purposes of veterinary medicine, e.g., in the case of domestic and working animals but also in the case of wild animals.
The administration can be carried out in the known way, for example, orally, topically, rectally, intravaginally, nasally or by injections. Oral administration is preferred. Compounds (1) are brought into a form that can be administered and are optionally mixed with pharmaceutically acceptable vehicles or diluents. The oral administration can be carried out, for example, in solid form as tablets, capsules, coated tablets or powders, but also in the form of a drinkable solution. The non-oral administration can be carried out by, for example, intravenous, subcutaneous or intramuscular injection or by ointments, creams or suppositories. An administration as a timed-release form can optionally also be carried out. The dosage can vary depending on the type of indication, the severity of the disease, the age, sex, body weight and sensitivity of the subject to be treated. Dosages of 0.01 to 30 mg, especially preferably 0.1 to 3 mg, and most preferably 0.1 to 1 mg per kg of body weight and per day are preferably administered. The administration can be carried out in an individual dose or several separate dosages.
Below, a number of especially preferred compounds (1) are listed:
In addition, the invention is to be explained by the following examples.